Design and synthesis of the tumor-activated prodrug of dihydropyrimidine dehydrogenase (DPD) inhibitor, RO0094889 for combination therapy with capecitabine

Article abstract of DOI:10.1016/S0960-894X(02)01082-X

A series of tumor-activated prodrugs of the inhibitors of dihydropyrimidine dehydrogenase (DPD), an enzyme catabolizing 5-fluorouracil (5-FU: 4g), has been designed and synthesized. RO0094889 (11c) is a prodrug of 5-vinyluracil (4c), a known DPD inhibitor

Full text of DOI:10.1016/S0960-894X(02)01082-X

Bioorganic & Medicinal Chemistry Letters 13 (2003) 867–872
Design and Synthesis of the Tumor-Activated Prodrug of
Dihydropyrimidine Dehydrogenase (DPD) Inhibitor, RO0094889
for Combination Therapy with Capecitabine
Kazuo Hattori,a Yasunori Kohchi,a Nobuhiro Oikawa,a Hitomi Suda,a Masako Ura,b
Tohru Ishikawa,b Masanori Miwa,b Mika Endoh,b Hiroyuki Eda,b Hiromi Tanimura,b
Akira Kawashima,c Ikuo Horii,c Hideo Ishitsukab and Nobuo Shimmaa,*
aDepartment of Chemistry, Nippon Roche Research Center, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan
bDepartment of Oncology, Nippon Roche Research Center, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan
cDepartment of Preclinical Science, Nippon Roche Research Center, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan
Received 30 September 2002; accepted 13 December 2002
Abstract—A series of tumor-activated prodrugs of the inhibitors of dihydropyrimidine dehydrogenase (DPD), an enzyme catabo-
lizing 5-fluorouracil (5-FU: 4g), has been designed and synthesized. RO0094889 (11c) is a prodrug of 5-vinyluracil (4c), a known
DPD inhibitor, and was designed to generate 4c selectively in tumor tissues by sequential conversion of 11c by three enzymes:
esterase, cytidine deaminase and thymidine phosphorylase, the latter two of which are known to be highly expressed in various
tumor tissues. When capecitabine (1), a tumor-activated prodrug of 5-FU, was co-administered orally with 11c, 5-FU in tumor
tissues was significantly increased with only a slight increase of 5-FU in plasma as compared with oral capecitabine alone.
# 2003 Published by Elsevier Science Ltd.
Introduction
a series of 50-deoxy-5-(substituted)-cytidine derivatives
as prodrugs of known DPD inhibitors so as to generate
an active DPD inhibitor, 5-(substituted)-uracil deriva-
tive5 selectively in tumors, similar to the design of
capecitabine.2 These cytidine derivatives were screened
for sequential activation by carboxylesterase, Cyd dea-
minase and dThdPase in vitro (Fig. 2). We identified
RO0094889 (11c) as a tumor-activated prodrug of
5-vinyluracil (5-VU: 4c). When both capecitabine and
11c were given orally, a much higher concentration of 5-
FU in tumor was attained without an increase in plasma
or other normal tissues as compared with oral capecita-
bine alone.
Previously, we designed an oral fluoropyrimidine, cape-
citabine (1),1,2 which generates 5-fluorouracil (5-FU: 4g)
selectively in tumors through its sequential metabolism
by three enzymes highly expressed in the liver and
tumors: carboxylesterase, cytidine deaminase (Cyd dea-
minase) and thymidine phosphorylase (dThdPase). The
susceptibility of human cancer xenografts to capecita-
bine correlated with the ratio of two enzymes in tumors,
dThdPase and dihydropyrimidine dehydrogenase
(DPD),3 which respectively generate 5-FU from the
intermediate 50-deoxy-5-fluorouridine (3: 50-DFUR) and
catabolize 5-FU to an inactive 5,6-dihydro-5-fluoro-
uracil (FUH2) (Fig. 1).
In this paper, we describe the discovery of RO0094889
as well as its potentiation of the antitumor activity of
capecitabine in vivo.
DPD exists in various types of human cancers.4 There-
fore, modulators of either dThdPase or DPD in tumors
would optimize capecitabine therapy. To enhance the
efficacy of capecitabine, but not its toxicity, we designed
Chemistry
After evaluation of known DPD inhibitors,5 we selected
the following six 5-substituted-uracil derivatives as par-
ent drugs with IC50 values of less than 1 mM: 4a (0.014
*Corresponding author. Tel.: +81-467-47-2280; fax: +81-467-45-
6824; e-mail: shinmanbo@chugai-pharm.co.jp
0960-894X/03/$ - see front matter # 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0960-894X(02)01082-X

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K. Hattori et al. / Bioorg. Med. Chem. Lett. 13 (2003) 867–872
Figure 1.
Figure 2.
mM),6 4b (0.22 mM),7 4c (0.089 mM), 4d (0.20 mM), 4e
(0.097 mM) and 4f (0.043 mM). These compounds were
either purchased or synthesized according to the proce-
dures in th0e literature.8 The synthesis of the corre-
sponding 5 -deoxyuridine, 50-deoxycytidine and N4-
alkoxycarbonyl-50-deoxycytidine derivatives are out-
lined in Figures 3 and 4. The 50-deoxyuridine deriva-
tives, 6a, 6b and 6e, were synthesized by glycosidation
reaction of 5-substituted uracil derivatives and 1,2,3-tri-
O-acetyl-5-deoxyribose with SnCl4, followed by hydro-
lysis of the acetyl group with NaOH in aqueous
methanol. The vinyl derivative (6c) was synthesized by
the Stille coupling reaction of 5b with tri-butylvinyl-
stanane, followed by hydrolysis of the acetyl group
under the same conditions. The cyano derivative (6d)
was synthesized by substitution reaction of the 5-iodo
derivative (7b) with sodium cyanide, followed by
removal of the TBS group with tetrabutylammonium
fluoride (TBAF). The (Z)-styryl derivative (6f) was
synthesized by palladium-catalyzed coupling reaction of
7b with phenylacetylene, followed by hydrogenation
with Lindlar catalyst and then removal of the TBS
group with TBAF. The 50-deoxycytidine derivatives (9a)
and (9e) were synthesized by treatment of the TBS
derivatives (7a and 7e respectively) with POCl3 in pyri-
dine/acetonitrile in the presence of dimethylaminopyr-
idine, followed by aminolysis with aqueous ammonia or
liquid ammonia and then removal of the TBS group
with HF-NEt3 or HF-pyridine.
The 50-deoxycytidine derivative (9b) was synthesized
from 5-iodocytosine (10) under similar reaction condi-
tions as the 50-deoxyuridine derivative (5b) as mentioned
above, followed by hydrolysis of the acetyl group with
NaOH in aqueous methanol. The cyano derivative (9d)
was synthesized from the 5-iodo derivative (8b) under
the same reaction conditions as the 50-deoxyuridine
derivative (6d). 20,30-Di-O-acetyl-50-deoxy-5-vinylcyti-
dine (11c: RO0094889) was synthesized from 11b under
the same reaction conditions as the 50-deoxyuridine
derivatives (6c) as mentioned above. The 50-deoxy-
cytidine derivative (9c) was prepared by hydrolysis of
11c with NaOH in aqueous methanol. The N4-penty-
loxycarbonyl-50-deoxycytidine derivatives, 12a, 12b, 12c
(RO0094226), 12d and 12e, were prepared by acylation of
the intermediates (8a–e and 11c) with n-pentyl chloro-
formate in pyridine/CH2Cl2, followed by removal of the
O-protecting group with TBAF (for the TBS group) or
K2CO3 in aqueous methanol (for the Ac group).
Results and Discussion
The 5-substituted-50-deoxycytidine derivatives synthe-
sized above were screened for sequential activation by
carboxylesterase/esterase,
Cyd
deaminase
and
dThdPase in vitro (Fig. 2). We selected the compounds
whose susceptibility to those enzymes were more than
0.1 relative to that of capecitabine (1), 50-DFCR (2) and

K. Hattori et al. / Bioorg. Med. Chem. Lett. 13 (2003) 867–872
869
Figure 3. Reagents: (A) Synthesis of 5a (starting from 4a): (i) HMDS, (NH4)2SO4, reflux, 5 h; (ii) 1,2,3-tri-O-acetyl-5-deoxyribose, SnCl4, CH3CN,
CH3NO2, 0 ꢀC, 2 h (64%, two steps); Synthesis of 5b (starting from 4b): (i) HMDS, (NH4)2SO4, benzene, reflux, 2 h; (ii) 1,2,3-tri-O-acetyl-5-deox-
yribose, SnCl4, CH3CN, CH3NO2, 0 ꢀC, 2 h (quant, two steps); Synthesis of 5e (starting from 4e): (i) HMDS, (NH4)2SO4, reflux, 5 h; (ii) 1,2,3-tri-O-
acetyl-5-deoxyribose, SnCl4, CH3CN, CH3NO2, 0 ꢀC, 3 h (89%, two steps); (B) Synthesis of 6a, 6b and 6e (starting from the corresponding 5):
NaOH, MeOH, H2O, 0 ꢀC, 0.5 h; (C) Synthesis of 7a (starting from 6a): TBSCl, imidazole, DMF, rt, 23 h (76% from 5a); Synthesis of 7b (starting
from 6b): TBSCl, imidazole, DMF, 60 ꢀC, 23 h (94% from 5b); Synthesis of 7e (starting from 6e): TBSCl, imidazole, DMF, rt, 23 h (quant. from 5e);
(D) Synthesis of 6d (starting from 7b): (i) NaCN, DMF, rt, 17 h; (ii) TBAF, THF, rt, 3 h (63% two steps); (E) Synthesis of 6f (starting from 7b): (i)
phenylacetylene, PdCl2(PPh3)2, CuI, NEt3, CH2Cl2, reflux, 6 h; (ii) H2, Lindlar cat., quinoline, hexane, rt, 36 h; (iii) TBAF, THF, rt, 1 h (12% three
steps); (F) Synthesis of 6c (starting from 5b): (i) vinyltributylstannane, Pd2(dba)3, tri-2-furylphosphine, DMF, rt, 96 h; (ii) NaOH, MeOH, H2O, rt,
0.5 h (49% two steps); (G) Synthesis of 8a (starting from 7a): POCl3, DMAP, pyridine, CH3CN, then NH4OH, 0 ꢀC to rt, 2 h (99%); Synthesis of 8e
(starting from 7e): POCl3, DMAP, pyridine, CH3CN, then liq.NH3, 0 ꢀC to rt, 2 h (75%); (H) Synthesis of 9a (starting from 8a): HF-NEt3, THF,
50 ꢀC, 14 h (80%); Synthesis of 9e (starting from 8e): HF-pyridine, THF, rt, 1 h (36%).
50-DFUR (3), respectively, in order to minimize the
release of an active DPD inhibitor in the blood stream
and to achieve the delivery of the prodrug to tumor tis-
sues. The enzyme conversion assays were carried out by
the same method described in our previous paper.9
evaluated for susceptibility to carboxylesterase from
human liver and intestine.
Table 3a shows the susceptibility of N4-alkoxycarbonyl-
50-deoxycytidine derivatives (12b and 12c) to carboxy-
lesterase, in which the conversion rates are expressed in
ng/mg protein/h. Between these two compounds, 5-vinyl
derivative (12c: RO0094226) showed a higher selectivity
to human liver carboxylesterase over intestinal carboxy-
lesterase (>22 times). The selectivity ratio of 12b was only
5. The potentiation effect of 12b on the antitumor activity
of capecitabine in human colon cancer xenograft (HCT
116) was inferior to that of 12c (data not shown). Thus, we
selected 5-vinyl derivative (12c) for further evaluation of
tumor selectivity and potentiation of the antitumor activ-
ity of capecitabine in other xenograft models. However, it
was found that 12c was chemically unstable, and easily
underwent dimerization through Diels–Alder cyclo-addi-
tion reaction between the vinyl group and the diene sys-
tem composed of the 5,6-double bond and the vinyl side
chain even at room temperature.10 This enabled us to
search for another chemically stable prodrug.
Table 1 shows the susceptibility of 50-deoxyuridine
derivatives, 6a–6f, to dThdPase with a value relative to
that of 50-DFUR (3). 5-Ethynyl- (6a) and 5-iodo- (6b)
uridine derivatives were 5, and 2.3 times more suscep-
tible to dThdPase than 50-DFUR, respectively. 5-Vinyl
derivative (6c) was 5 times less susceptible than
50-DFUR. 5-Cyano- (6d), 5-(3-benzyloxybenzyl)- (6e)
and 5-(Z)-styryl- (6f) uridine derivatives were not sus-
ceptible to dThdPase. Thus, 6a, 6b and 6c were selected
and converted to the corresponding cytidine derivatives
(9a–c). The compounds (9a–c) were then evaluated for
the susceptibility to Cyd deaminase.
Table 2 shows the susceptibility of 50-deoxycytidine
derivatives (9a–c) to Cyd deaminase, with a value rela-
tive to that of 50-DFCR (2). Among them, the suscept-
ibility of 5-iodo derivative (9b) and 5-vinyl derivative
(9c) were more than 0.1 relative to that of 50-DFCR (2).
The 5-ethynyl derivative (9a) was the least susceptible
among them. Thus, 9b and 9c were selected and con-
verted to the corresponding N4-alkoxycarbonyl-50-
deoxycytidine derivatives (12b and 12c), which were
We examined the possibility of 20,30-di-O-acetyl-50-
deoxy-5-vinylcytidine (11c: RO0094889) as an alter-
native prodrug. Interestingly, the crystalline form of 11c
was chemically stable and its stability was better than
the corresponding deacetyl derivative (9c).10

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K. Hattori et al. / Bioorg. Med. Chem. Lett. 13 (2003) 867–872
Figure 4. (I) Synthesis of 11b (starting from 10): (i) HMDS, toluene, reflux, 3 h; (ii) 1,2,3-tri-O-acetyl-5-deoxyribose, TiCl4, CH2Cl2, 0 ꢀC, 2 h (78%,
two steps); (J) Synthesis of 9b (starting from 11b): NaOH, MeOH, 0 ꢀC, 0.5 h (quant); (K) Synthesis of 8b (starting from 9b): TBSCl, imidazole,
DMF, 60 ꢀC, 3 h (quant); (L) Synthesis of 9d (starting from 8b): (i) NaCN, DMF, rt, 24 h; (ii) TBAF, THF, rt, 0.5 h (44% two steps); (M) Synthesis
of 11c (starting from 11b): vinyltributylstannane, Pd2(dba)3, tri-2-furylphosphine, DMF, rt, 96 h (86%); (N) Synthesis of 9c (starting from 11c):
NaOH, MeOH, H2O, 0 ꢀC, 0.5 h (98%); (O) Synthesis of 12a (starting from 8a): (i) n-pentyl chloroformate, pyridine, CH2Cl2, rt, 2 h; (ii) TBAF,
THF, rt, 2 h (58%, two steps); Synthesis of 12b (starting from 8b): (i) n-pentyl chloroformate, pyridine, CH2Cl2, rt, 1 h; (ii) TBAF, THF, rt, 2 h
(80%, two steps); Synthesis of 12d (starting from 8d): (i) n-pentyl chloroformate, pyridine, CH2Cl2, rt, 2 h; (ii) TBAF, THF, rt, 3 h (91%, two steps);
Synthesis of 12e (starting from 8e): (i) n-pentyl chloroformate, pyridine, DMAP, CH2Cl2, rt, 2 h; (ii) TBAF, THF, rt, 2 h (45%, two steps); (P)
Synthesis of 12c (starting from 11c): (i) n-pentyl chloroformate, pyridine, CH2Cl2, rt, 2 h; (ii) K2CO3, MeOH, H2O, rt, 0.5 h (85%, two steps).
Table 2. Susceptibility of 5-substituted cytidine derivatives to Cyd
deaminase
Table 1. Susceptibility of 5-substituted uridine derivatives to
dThdPase
Compd.
X
Relative susceptibilitya
(analogues/50-DFUR)
Compd.
X
Relative susceptibilitya
(analogues/50-DFCR)
6a
5.0
2.3
9a
0.034
6b
9b
9c
I
0.33
0.14
6c
0.20
<0.01
<0.01
<0.01
1
50-DFCR (2)
F
1
6d
aConcn of the substrate: 2.0 mM.
6e
enzyme than intestinal enzyme (crude enzyme extract):
the susceptibility to human liver and intestinal enzymes
were 130 and 28 nmol/mg protein/h, respectively.
6f
50-DFUR (3)
F
The tumor-selective delivery of active DPD inhibitor, 5-VU,
by oral RO0094889 in vivo, and tumor-selective increase
of 5-FU concentration by its co-administration with
capecitabine
aConcn of the substrate: 1.0 mM.
As shown in Table 3b, compound 11c was also stable in
aqueous solution at pH 2.0–7.4 for 2 h (37 ꢀC). The
diacetate group of 11c could be rapidly hydrolyzed by
the esterase mainly in the liver after oral absorption
since 11c is 4.6 times more susceptible to human liver
The tumor selective delivery of the active DPD inhib-
itor, 5-vinyluracil was demonstrated by the following
experiment in vivo (Fig. 5). RO0094889 (33.7 mg/kg)

K. Hattori et al. / Bioorg. Med. Chem. Lett. 13 (2003) 867–872
871
Table 3. Susceptibility of N4-alkoxycarbonyl-5-substituted-50-deoxycytidine and 20,30-O-diacetyl-5-substituted-50-deoxycytidine derivatives to
human carboxylesterase and esterase, respectively
(a)
(b)
Compd.
X
Susceptibilitya to carboxylesterase (nmol/mg protein/h)
RO0094889 (11c)
* Susceptibility to esterase (nmolmg protein/h)
Liver (L)
Intestine (I)
Ratio L/I
12b
12c: RO0094226
I
90
110
18
<5.0
5
>22
Human liver
intestine
(130)
(28)
Capecitabine (1)
F
79
5.3
15
* Stability in serum
61%
(remaining % after 1 h)
(remaining % after 2 h)
* Stability at pH 2.0–7.4
100%
aConcn of the substrate: 2.5 mM.
and capecitabine (135 mg/kg) given orally to a HT-3
human cervical cancer xenograft generated high 5-VU
levels in tumors (2.2 nmol/g) and the local administra-
tion site intestine (2.0 nmol/g), but only low levels in
other normal tissues studied (<0.6 nmol/g). In contrast,
5-VU itself was not tumor-selective and gave 5-VU at
much higher concentrations in the stomach and intes-
tine than in tumors. Since the uridine phosphorylase11
activity in mouse intestine is known to be 17 times
higher than dThdPase activity in human, the exposure
of 5-VU at intestine in human is expected to be lower.
As a result of this tumor-selective delivery of active DPD
inhibitor by RO0094889, a significant increase of 5-FU
concentration in tumor tissues can be achieved when both
capecitabine (1) and RO0094889 are given orally (Table
4). Capecitabine (135 mg/kg) alone or in combination with
either 5-VU (1.38 mg/kg) or RO0094889 (33.7 mg/kg) was
given orally to mice bearing HT-3 human cervical cancer.
At various time points, tumor and plasma levels of 5-FU
were determined by LC/MS/MS. As seen in Table 4, the
combination of RO0094889 and capecitabine significantly
increased the Cmax of 5-FU in tumor with only a slight
Table 4. 5-FU levels in tumor and plasma after treatment with
capecitabine+5-vinyluracil versus capecitabine+RO0094889 (HT-3
human cervical cancer xenograft)
Compd
5-FU Cmax (nmol/mL or g) Ratio T/P
Tumor (T)
Plasma (P)
Capecitabine
Capecitabine+5-vinyluracil
Capecitabine+RO0094889
3.5
12
13
0.62
3.2
1.0
5.6
3.8
13
Capecitabine (135 mg/kg) alone or in combination with either 5-VU
(1.38 mg/kg) or RO0094889 (33.7 mg/kg), was given orally. At various
time points, tumor and plasma levels of 5-FU were determined by LC/
MS/MS.
Figure 5. Tumor selective delivery of active DPDi, 5-VU, by
RO0094889 (po): (HT-3 human cervical cancer xenograft).
Figure 6. Antitumor activity of capecitabine with RO0094889: (a) NCl-H460 human NSCLC xenograft; (b) Calu-3 human NSCLC xenograft.

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K. Hattori et al. / Bioorg. Med. Chem. Lett. 13 (2003) 867–872
Figure 7. Sequential bioconversion of RO0094889 to 5-VU.
2. Shimma, N.; Umeda, I.; Arasaki, M.; Murasaki, C.;
Masubuchi, K.; Kohchi, Y.; Miwa, M.; Ura, M.; Sawada, N.;
Tahara, H.; Kuruma, I.; Horii, I.; Ishitsuka, H. Bioorg. Med.
Chem. 2000, 8, 1697.
increase of 5-FU in plasma, as compared with adminis-
tration of capecitabine alone. This selectivity was not
observed in the combination of capecitabine with 5-VU.
3. Ishikawa, T.; Sekiguchi, F.; Fukase, Y.; Sawada, N.; Ishit-
suka, H. Cancer Res. 1998, 58, 685.
4. Naguib, F. N. M.; El Kouni, M. H.; Cha, S. Cancer Res.
1985, 45, 5405.
Enhancement of antitumor activity of capecitabine in
combination with RO0094889 in human non-small cell
lung carcinoma (NSCLC) xenografts
5. (a) Naguib, F. N. M.; El Kouni, M. H.; Cha, S. Biochem.
Pharmacol. 1989, 38, 1471. (b) Baccanani, D. P.; Davis, S. T.;
Knick, V. C.; Spector, T. Proc. Natl. Acad. Sci. U.S.A. 1993,
90, 11064. (c) Shirasaka, T.; Shimamato, Y.; Ohshimo, H.;
Yamaguchi, M.; Kato, T.; Yonekura, K.; Fukushima, M.
Anti-Cancer Drugs 1996, 7, 548.
In the NCI-H460 human NSCLC xenograft, a combi-
nation of capecitabine (377 mg/kg) and RO0094889
(10.1 mg/kg) given orally five times a week for 2 weeks
resulted in a significant increase of tumor growth inhi-
bition as compared with that of the same dose of cape-
citabine alone (Fig. 6a).
6. Porter, D. J. T.; Chestnut, W. G.; Merrill, B. M.; Spector,
T. J. Biol. Chem. 1992, 267, 5236.
7. Porter, D. J. T.; Chestnut, W. G.; Taylor, L. C. E.;
Merrill, B. M.; Spector, T. J. Biol. Chem. 1991, 266,
19988.
8. (a) Perman, J.; Sharma, R. A.; Bobek, M. Tetrahedron Lett.
1976, 28, 2427. Synthesis of 4a. (b) Farina, V.; Hauck, S. I.
Synlett 1991, 157. Synthesis of 4c. (c) Orr, G. F.; Musso, D. L.;
Boswell, G. E.; Kelly, J. L.; Joyner, S. S.; Davis, S. T.; Bac-
canari, D. P. J. Med. Chem. 1995, 38, 3850. Synthesis of 4e. (d)
Synthesis of 4f: This compound was synthesized from 4b
according to the same as procedure for 6f.
9. Miwa, M.; Ura, M.; Nishida, M.; Sawada, N.; Ishikawa,
T.; Mori, K.; Shimma, N.; Umeda, I.; Ishitsuka, H. Eur. J.
Cancer 1998, 34, 1274.
10. The remaining amount (%) of 12c, 9c and 11c in crystal-
line form at room temperature after 7 days were 91, 95 and
>99.9%, respectively.
As mentioned before, antitumor activity of capecitabine
is influenced by the ratio of dThdPase and DPD.
Therefore, the combination of both dThdPase up-reg-
ulator and DPD inhibitor is expected to maximize the
antitumor activity of capecitabine as a result of a max-
imum increase of 5-FU concentration in tumor tissues.
Ishitsuka et al. reported taxotere up-regulates dThdPase
in tumors.12 Thus, the following triple combination was
investigated (Fig. 6b). In the Calu-3 human NSCLC
xenograft, a triple combination of capecitabine (269 mg/
kg/day, po), RO0094889 (10.1 mg/kg/day, po) plus tax-
otere (7.5 mg/kg/weekly, iv) showed more than additive
tumor growth inhibition as compared with that of the
same dose of capecitabine plus RO0094889 (Fig. 6b).
11. Miwa, M.; Cook, A.; Ishitsuka, H. Chem. Pharm. Bull.
1986, 34, 4225.
In conclusion, RO0094889 generates the DPD inhibitor
5-VU preferentially in tumors by the same enzymes as in
capecitabine activation. The combination of RO0094889
and capecitabine is therefore expected to give the active
compounds selectively in tumor tissues and show better
efficacy against tumors that express high DPD levels,13
such as NSCLC,14 than capecitabine alone (Fig. 7).
12. Sawada, N.; Ishikawa, T.; Fukase, Y.; Nishida, M.;
Yoshikubo, T.; Ishitsuka, H. Clin. Cancer Res. 1998, 4, 1013.
13. Mori, K.; Hasegawa, M.; Nishida, M.; Toma, H.;
Fukuda, M.; Kubota, T.; Nagase, N.; Yamana, H.; Hirakawa-
YS, C. K.; Ikeda, T.; Takasaki, K.; Oka, M.; Kameyama, M.;
Toi, M.; Fujii, H.; Kitamura, M.; Murai, M.; Sasaki, H.;
Ozono, S.; Makuuchi, H.; Shimada, Y.; Onishi, Y.; Aoyagi,
S.; Mizutani, K.; Ogawa, M.; Nakao, A.; Kinoshita, H.; Tono,
T.; Imamoto, H.; Nakashima, Y.; Manabe, T. Int. J. Oncol.
2000, 17, 33.
References and Notes
14. Huaug, C. L.; Yokomise, H.; Kobayashi, S.; Fukush-
ima, M.; Hitomi, S.; Wada, H. Int. J. Oncol. 2000, 17,
47.
1. Ishikawa, T.; Utoh, M.; Sawada, N.; Nishida, M.; Fukase, Y.;
Sekiguchi, F.; Ishitsuka, H. Biochem. Pharmacol. 1998, 55, 1091.